Cystic fibrosis is a genetically inherited life-limiting disorder that affects 30,000 people in the US and 70,000 people worldwide. Increased mucus viscosity in the lungs of CF-afflicted individuals prevents the clearance of bacteria via normal means (e.g., ciliary beating and coughing), thereby allowing proliferation and the formation of biofilms. Bacterial biofilms degrade the lungs and are the primary cause of CF morbidity and mortality. While gene therapies could potentially cure CF, there are over 1,800 genetic mutations which cause CF, each of which would require the development of a specific drug. Therefore, development of therapeutics that are more effective than current treatments at eliminating bacterial biofilms represents a more cost effective and timely approach to increasing the life expectancy of people with CF. The goal of this project is to develop water soluble chitosan scaffolds that release nitric oxide (NO), an endogenous antibacterial agent, and effectively eradicate CF biofilms. The efficacy of these novel NO-release scaffolds will be tested against CF-relevant bacteria strains in conditions that mimic the CF lung. We hypothesize that disulfide-reducing reactivity of NO will also reduce the mucus viscosity, potentially enhancing the action of subsequent NO treatments and improving the ability of the innate immune system to further control bacterial levels in the lungs. The effects of NO and NO-release scaffold composition on mucus viscosity will thus be systematically studied to determine NO's potential as a dual action CF therapeutic. These macromolecular scaffolds represent the first NO-based therapeutics suitable for pulmonary delivery, and are thus highly innovative.